Molecular, biological characterization and drug sensitivity of chidamide‑resistant non‑small cell lung cancer cells

Abstract

Abstract. Chidamide, a histone deacetylase (HDAC) inhibitor, has been applied in clinical trials for various types of hematological and solid tumors. Although acquired resistance is common in chemotherapy, the mechanism of resistance to chidamide is poorly characterized. The goal of the present study was to explore, in detail, the mechanism for the induced resistance to chidamide, and investigate a potential cross-resistance to other chemotherapeutic drugs. A549 cells were exposed to gradually increasing chidamide concentrations to establish a chidamide-resistant non-small cell lung cancer cell line (A549-CHI-R). The IC 50 for chidamide, the proliferation inhibition rate, the total HDAC activity and the HDAC protein level were determined by an MTT assay, colony formation, a fluorometric HDAC activity assay and western blotting, respectively. Overexpression of the HDAC1 gene and HDAC1 gene-knockdown were achieved via plasmid transfection. A549-CHI-R cells demonstrated increased resistance to chidamide (8.6-fold). HDAC1 protein degradation was inhibited and HDAC activity was significantly higher in the A549-CHI-R cells relative to the parental A549 cells. A549-CHI-R cells demonstrated cross-resistance to paclitaxel, vinorelbine and gemcitabine, but not to cisplatin (CDDP) or 5-fluorouracil (5-FU). These results indicated that HDAC1 may be associated with resistance to chidamide, and HDAC1 may therefore be a predictive marker for chidamide sensitivity in cancer. In addition, A549-CHI-R cells remained sensitive to 5-FU and CDDP, indicating a potential strategy for cancer therapy.

Inhibition of HDAC and Signal Transduction Pathways Induces Tight Junctions and Promotes Differentiation in p63-Positive Salivary Duct Adenocarcinoma

“…The following four classes of the HDAC family are currently known: class I HDACs (HDAC 1-3, and 8), class II HDACs (HDAC 4–7, 9, and 10), class IV (HDAC 11), and class III (sirtuin family: SIRT1-7) [ 21 , 23 ]. To date, different HDACs have been shown to be abundantly expressed in various human cancers such as laryngeal, gastric, liver, colon, breast, lung, and salivary gland cancers [ 24 , 25 , 26 ]. In salivary gland tumors, the expression of HDAC6 is correlated with a poor prognosis [ 26 ].…”

Chidamide Suppresses the Growth of Cholangiocarcinoma by Inhibiting HDAC3 and Promoting FOXO1 Acetylation

“…According to previous reports, CDM inhibits the proliferation of glioma cells, lung cancer, pancreatic cancer, and myeloma cells [24][25][26]. In Jurkat and HUT-78 cells, treatment with CDM (2 μM) leads to downregulation of HDAC3 expression, thus inducing necroptosis [27].…”

Chidamide and Radiotherapy Synergistically Induce Cell Apoptosis and Suppress Tumor Growth and Cancer Stemness by Regulating the MiR-375-EIF4G3 Axis in Lung Squamous Cell Carcinomas

“…In December 2014, chidamide has been approved by the China Food and Drug Administration (CFDA) as a treatment strategy for peripheral T-cell lymphoma (PTCL) [5]. Interestingly, accumulating studies have demonstrated that chidamide shows an effective antitumor activity in multiple solid tumors, including liver cancer, colon carcinoma, and lung cancer [6][7][8][9][10][11]. In lung cancer, Hu et al have performed a phase I trial of chidamide combined with paclitaxel and carboplatin in patients with advanced NSCLC and found that a combination treatment of chidamide and paclitaxel or carboplatin was tolerated without unanticipated toxicities or pharmacokinetic interactions [6].…”